Like proteins and carbohydrates, lipids are a category of essential elements of li ving cells. Lipids play multiple physiological roles in all types of cells in a wide range of living species. In addition to their basic functions in energy metabolism/storage and formation of membranes and sub-cellular components, lipid molecules are important for cell-cell communication, cell signaling and intracellular signal transduction.
Lipid molecules of diverse structures are also an important target for immunologic recognition, such as the specific host recognition of microorganisms that are mediated by microbe-specific lipid or lipid-containing molecules. A major histocompatibility (MHC)-like protein, CD1, binds certain types of lipid molecules and presents them to T cells or NK cells [1, 2]. This unique antigen presentation system presents lipid antigens to effector T cells, which have diverse roles in anti-microbial responses, anti-tumor immunity and the regulation of the balance between tolerance and autoimmunity. Many bacterial pathogens produce phospholipids, glycolipids and/or lipopolysaccharides of distinct antigenic structures. Some are specific for given pathogen and thereby serve as biomarkers for pathogen identification and diagnosis of infectious diseases, and as vaccine targets for the induction of anti-infection immune responses.
Lipid moieties of cellular components may also be molecular targets of autoimmune diseases [3, 4]. In multiple sclerosis (MS) and autoimmune encephalomyelitis (EAE), there are increased T cell and autoantibody reactivities that are directed at myelin lipids [3-5]. These autoimmune responses are responsible for demyelination in central and/or peripheral neural tissues. In systemic lupus erythematosus (SLE), anti-cardiolipin antibodies were detected in addition to the autoantibodies to protein and nucleic acid components that were previously recognized [6]. CD1 expression is increased at the site of brain lesions in both MS and its rodent model, experimental autoimmune encephalomyelitis (EAE) [7-9].
Lipid-based antigenic cross-reactivities or molecular mimicry between cellular components and specific microbial antigens may contribute to either pathogenesis of infectious diseases or clearance of cellular lipid products [10-12]. Campylobacter jejuni infection induced an autoimmune neurological disorder Guillain-barre syndrome in a considerable proportion (˜⅓) of cases [3, 4, 13]. This pathogen expresses a lipopolysaccharide molecule that mimics various gangliosides present in high concentrations in peripheral nerves. Infection by this bacterium may, thus, elicit undesired autoimmune responses to gangliosides of the host tissue. In addition, numerous viral infections induce this syndrome, since viruses collect gangliosides as they incorporate plasma membrane from the host cell. Therefore, precaution must be taken when we consider the use of the whole-viral preparations that are made by human or primate cells as vaccine candidates. Such vaccines may display the host-tissue derived lipid and glycolipid structures with altered antigenic reactivity and thus elicit undesired autoimmune responses.
Self-lipid components may be modified to generate neo-immunogenic lipid epitopes [14, 15]. For example, oxidation of low-density lipoprotein (LDL) generates a variety of oxidatively modified lipids and lipid-protein adducts that are immunogenic and proinflammatory, which in turn contribute to atherogenesis. Cells undergoing apoptosis also display oxidized moieties on their surface membranes, as determined by binding of oxidation-specific monoclonal antibodies. However, lipid-elicited autoantibodies are not always harmful. Some anti-lipid autoantibodies play roles in the clearance of non-essential or harmful cellular lipid derivatives and are, in fact, beneficial to the hosts [11, 15, 16]. In such circumstance, a microbial antigen may share structural similarity with the moieties of the latter category of cellular lipid derivatives and elicits the “beneficial autoantibodies” to bind and remove the “junk lipids” from the circulation. For example, there is molecular mimicry between Streptococcus pneumoniae and oxidized low-density lipoprotein (oxLDL) [15]. Immunization with cell-wall polysaccharide of Streptococcus pneumoniae elicited T15 anti-phosphorylcholine antibodies that cross-react with oxidized epitopes of low-density lipoprotein (oxLDL). The elevated LDL level is positively correlated to the progression of atherosclerosis and oxLDL has been identified in atherosclerotic lesions. Pneumococcal vaccination induced high circulating levels of oxLDL-specific IgM and decreased the extent of atherosclerosis in animal models [15].
Howe et al [16] reported that a human monoclonal IgM antibody directed against myelin induces antiapoptotic signaling in premyelinating oligodendrocytes and reduces caspase-3 activation and caspase gene expression in mice undergoing antibody-induced remyelination. Such autoantibody-mediated signaling may have important therapeutic implications for a variety of neurological diseases, including stroke and Alzheimer's disease.
In summary, lipids represent an important class of antigenic structures and have unique physiochemical properties. In view of their antigenic reactivities, there are two major categories of lipids: microbe-specific structures and host-tissue cross-reactive moieties. The former are able to induce pathogen-specific immune responses and are considered as candidate molecules for developing vaccines or diagnostic tool to combat infectious diseases. The latter may play roles in regulating the biological relationship of microbes and their hosts and in certain circumstances the induction of autoimmune responses. Some anti-self-lipid activities are, however, beneficial to the hosts. The outcome of an anti-lipid antibody response depends on multiple factors, including epitope-binding specificity of anti-lipid antibodies, tissue and subcellular distribution of lipid molecules, and the physiological and pathophysiological properties of the targeted lipid molecules.